PROJECT SUMMARY/ABSTRACT The overall goal of this K99/R00 application is to examine the age-related changes in cerebral vasodilatory capacity, and how this is mechanistically linked to cognition. This application will explore the potential beneficial effect of physical activity on the relationships between vasodilatory capacity and emerging biomarkers of cognitive decline. Furthermore, this project will serve as a vehicle to build upon the applicant's training in cardiovascular aging and exercise physiology and her recently completed F32 funded work by allowing her to learn additional techniques including fMRI image analysis and interpretation of neuropsychological testing. Recent evidence suggests that cerebral microvascular dysfunction declines with advancing age, and may precede the onset of cognitive impairment. Aging is associated with greater white matter hyperintensity (WMH) volume and also alters functional connectivity of the default mode network (DMN) which is linked to executive functioning processes. Additionally, physical activity is associated with higher cerebral blood flow velocity and improved cognitive function which may be linked to the ability to match metabolism and perfusion. However, information mechanistically linking cerebral vasodilator function and cognition is lacking. It is currently unclear if aging or exercise training status alters the neurovascular coupling of blood flow with neural activity in the brain. Therefore, we aim to systematically test the hypothesis that cerebral microvascular function is blunted in aging humans and improved with habitual exercise. We will also determine if cerebral vasodilator responses are associated with WMH volume and functional connectivity of the DMN. Collectively, these studies will offer insight into the underlying changes in cerebral microvascular function and explore how they are functionally linked to cognition with potential relevance to the development and prevention of cognitive impairment. In Aim 1, we will compare cerebral vasodilator responses to chemical and metabolic stimuli before and after cyclooxygenase inhibition and determine how these correlate with cognitive function in: 1) young healthy adults; 2) sedentary older adults; and 3) exercise trained older adults. In Aim 2, we will determine if WMH volume in the brain is affected by aging and habitual exercise and if the cerebral vasodilator responses are associated with WMH volume in the same three groups as in Aim 1. In Aim 3, we will determine if aging and habitual physical activity affects DMN connectivity in the brain in the same three groups studied in Aim 1. In summary, we have proposed a sequence of experiments that focus on the mechanistic link between cerebral vasodilator responses, WMH volume, and functional connectivity of the DMN, all of which are potential biomarkers of risk of cognitive decline. These projects will extend the applicant's training by incorporating neuropsychological testing interpretation and advanced fMRI image analysis. In addition, potential follow-up studies have been identified that will be key elements in the applicant's career progression and foster her development as an independent investigator.